Cell:cell interactions are mediated by a variety of cell surface proteins including intercellular adhesion molecule-1 (ICAM-1). ICAM-1-mediated events, whether mediated directly or indirectly, include such biological significant processes as leukocyte transmigration, T cell activation and inflammatory injury (for reviews, see Bierer et al., FASEB J., 1988, 2, 2584; Makgoba et al., Immunol. Today, 1989, 10, 417; Dustin et al., Annu. Rev. Immunol., 1991, 9, 27; and Albelda et al., FASEB J., 1994, 8, 504).
The adhesion of white blood cells to vascular endothelium and other cell types is mediated by interactions between specific proteins, termed "adhesion molecules," located on the plasma membrane of both white blood cells and vascular endothelium. The interaction between adhesion molecules is similar to classical receptor ligand interactions with the exception that the ligand is fixed to the surface of a cell instead of being soluble. The identification of patients with a genetic defect in leukocyte adhesion has enabled investigators to identify a family of proteins responsible for adherence of white blood cells. Leukocyte adhesion deficiency (LAD) is a rare autosomal trait characterized by recurrent bacterial infections and impaired pus formation and wound healing. The defect was shown to occur in the common B-subunit of three heterodimeric glycoproteins, Mac-1, LFA-1, and p150,95, normally expressed on the outer cell membrane of white blood cells (Anderson et al., Ann. Rev. Med., 1987, 38, 175). Patients suffering from LAD exhibit a defect in a wide spectrum of adherence-dependent functions of granulocytes, monocytes, and lymphocytes. Three ligands for LFA-1 have been identified, intercellular adhesion molecules 1, 2 and 3 (ICAM-1, ICAM-2 and ICAM-3). Mac-1 and p150,95 both bind complement fragment C3bi and, perhaps, other unidentified ligands; Mac-1 also binds ICAM-1.
Expression of ICAM-1 has been associated with a variety of inflammatory skin disorders such as allergic contact dermatitis, fixed drug eruption, lichen planus and psoriasis (Ho et al., J. Am. Acad. Dermatol., 1990, 22, 64; Griffiths et al., Am. J. Pathology, 1989, 135, 1045; Lisby et al., Br. J. Dermatol., 1989, 120, 479; Shiohara et al., Arch. Dermatol., 1989, 125, 1371). In addition, ICAM-1 expression has been detected in the synovium of patients with rheumatoid arthritis (Hale et al., Arth. Rheum., 1989, 32, 22), in pancreatic B-cells in diabetes (Campbell et al., Proc. Natl. Acad. Sci. U.S.A., 1989, 86, 4282) and in thyroid follicular cells in patients with Graves' disease (Weetman et al., J. Endocrinol., 1989, 122, 185), and has been associated with renal and liver allograft rejection (Faull et al., Transplantation, 1989, 48, 226; Adams et al., Lancet, 1989, 1122).
It is has been hoped that inhibitors of ICAM-1 would provide a novel therapeutic class of anti-inflammatory agents with activity towards a variety of inflammatory diseases or diseases with an inflammatory component such as asthma, rheumatoid arthritis, allograft rejections, inflammatory bowel disease, various dermatological conditions, and psoriasis. In addition, inhibitors of ICAM-1 may also be effective in the treatment of colds due to rhinovirus infection, AIDS, Kaposi's sarcoma and some cancers and their metastasis. The use of neutralizing monoclonal antibodies against ICAM-1 in animal models has provided evidence that inhibitors of ICAM-1, if identified, would have potential therapeutic benefit for asthma (Wegner et al., Science, 1990, 247, 456), renal allografts (Cosimi et al., J. Immunol., 1990, 144, 4604) and cardiac allografts (Isobe et al., Science, 1992, 255, 1125). Moreover, a soluble form of ICAM-1 molecule was effectively used to prevent rhinovirus infection of cells in culture (Marlin et al., Nature, 1990, 344, 70).
There remains a need for therapeutic agents with an enhanced ability to effectively prevent the expression of ICAM-1. Current agents which affect cellular adhesion molecules include monoclonal antibodies and polypeptide soluble forms of the ligands of adhesion molecules. Monoclonal antibodies to ICAM-1 may prove to be useful for the treatment of acute inflammatory response due to expression of ICAM-1, however, with chronic treatment, the host animal can develop an immune response against the anti-ICAM-1 antibodies, thereby limiting their usefulness. In addition, antibodies are large proteins which may have difficulty in gaining access to the inflammatory site. Polypeptide forms of the cell adhesion molecules suffer from many of the same limitations as antibodies in addition to the expense of their production and their low binding affinity. Antisense compounds avoid many of the pitfalls of other agents that could potentially be used to block the effects of ICAM-1. The present invention is drawn to chemically modified antisense oligonucleotides having an enhanced ability to modulate ICAM-1.